Methods known in the art for the synthesis of metyrapone generally include two-steps. The first step involves the preparation of a pinacol substrate generally formed from two equivalents of 3-acetylpyridine substrate. A symmetric compound, 2,3-dipyridine-3-yl-2,3-butanediol, is formed, in a reaction which involves the formation of two adjacent quaternary centers. In general, the formation of quaternary centers is made more difficult by the presence of large substituent groups at the potential quaternary carbon atoms. In the case of the reaction above, each potential quaternary carbon bears a pyridine substituent and a carbonyl oxygen in addition to a methyl group. Such substituents, particularly a group as bulky as pyridine, hinder the formation of the quaternary center. It is thus necessary to use another method in which the first step, which forms two such centers adjacent each other, is generally run at extreme or unusual conditions. An electrochemical step or a chemical step involving mercury or mercury salts is most commonly used.
The second step involves the rearrangement reaction of 2,3-dipyridine-3-yl-2,3-butanediol. As with the first step, the second step is fraught with problems which reduce the yield. In rearrangement reactions, a substituent shifts carbon centers. In the case of 2,3-dipyridine-3-yl-2,3-butanediol, one of two groups (pyridine, methyl) can undergo the shift. The desired product, metyrapone, is formed with significant amounts of a ketone byproduct, which reduces metyrapone yield and purity. Resolution of the resultant mixture is necessary. One method of resolution is the separation of the metyrapone and ketone byproduct by chromatographic methods. Another method involves derivatization as an oxime, followed by crystallization of the derivative, with a final hydrolysis step to give metyrapone. Both resolution methods contribute to a lowering of the yield of metyrapone.
The formation of 2,3-dipyridine-3-yl-2,3-butanediol, and the subsequent rearrangement reaction are illustrated below:

Literature publications in the late 1990's demonstrated that carbon-to-carbon bond connections could be made with palladium-catalyzed reactions using halogenated aromatic compounds. Various methods of preparing similar compounds have been tried. For example, a publication authored by Kawatsura and Hartwig (J. Am Chem. Soc., Vol. 121. No. 7, 1999), discloses the alpha arylation of ketones with aryl bromides with the use of palladium containing catalysts. The reference also discloses the formation of a quaternary carbon centers, albeit without the use of heterocyclic reactants.
However, the palladium catalyzed arylations of ketone alpha carbon atoms, particularly to form a quaternary center at the alpha carbon, are beset with unpredictability for at least two reasons. First, palladium catalysts are known to participate in the formation of ligand complexes with nitrogen containing heterocyclic aryl groups. Furthermore, some compounds containing multiple ligand-forming heterocycles such as pyridine are known to form particularly stable complexes with palladium-containing catalysts due to the “chelate effect.” Metyrapone is part of this group in that metyrapone includes two pyridine groups. Such complexes are expected to interfere with or prevent the formation of necessary intermediate complexes involving the palladium catalyst and the reactant molecules. The chelate effect refers to the enhanced stability of chelate complexes (metal/ligand complexes derived from multidentate ligands), as opposed to complexes derived from one or more monodentate ligands. In its fully bonded state, the chelating ligand at least partially surrounds the central atom. The ligand need not have the same number of ligating groups as the number of bonding metal orbitals. For example, the notably stable dimethylglyoximate complex of nickel is a synthetic macrocycle derived from the anion of dimethylglyoxime. Nickel has four bonding sites and the ligand consists of two dimethylglyoxime molecules having two ligands each. The chelate structure is a central atom at the center of a ring structure. It is generally recognized that the chelate effect greatly stabilizes chelates with respect to mono-ligand containing complexes, and the enhanced stability favors the displacement of a number of monodentate ligands by a smaller number of polydentate ligands. In the case of using the reaction in the reference to form metyrapone, the indicated reaction would be the alpha arylation of 3-isobutyryl pyridine with a 3-halopyridine. One of skill in the art would recognize that the metyrapone product, a molecule having two pyridines, each of which are capable of bonding to one of the six palladium bonding orbitals, could be a suitable chelating ligand, according to common chemical knowledge. In such a case, the reaction would not be expected to proceed because the first molecules of product would form stable complexes with the catalyst, resisting displacement by reactant molecules, which are monodentate.
Yet a further factor which is expected to help the ability of the product to employ all of its pyridine groups is their relative placement. The length of the linking groups between the pyridine groups can be too short or too bulky to permit efficient coordination of all the pyridine groups.
The second reason the results of palladium-catalyzed arylations can be difficult to predict is that the use of palladium catalysts is subject to steric constraints that are not well-understood. The degree to which a palladium catalyst effects the arylation, if arylation even occurs at all, can depend critically upon the particular palladium catalyst, auxiliary ligands, the size of the alkanyl substituent to be arylated, as well as the base, and even the solvent. Thus, regardless of the possibility of product/catalyst interaction, the reaction may only produce an insignificant amount of product, if any at all. For example, the experiment of Example Ib essentially reproduces a run from (Biscoe & Buchwald, Organic Letters, 11, 1773 (2009)), except for the use of 3-isobutyrylpyridine as a reactant (in an attempt to form metyrapone) rather than 3-acetylpyridine as used in the reference. No product was observed, despite the fact that the reference reaction did form product. With the substitution, the reaction does not proceed at all, even with the same catalyst and under the same conditions as used in the reference. Furthermore, the lack of product tends to indicate that the lack of reaction was not due to catalyst chelation, but rather the difficulty in forming the quaternary center necessary for the formation of metyrapone. Thus, reaction success can depend upon steric characteristics of the two reactants.
Metyrapone, a commercial product of high value long before the publication of the coupling methods described above, is presently prepared through the two-step process described above, despite relatively low yields and high amounts of byproduct impurities. A process which can prepare poly-heterocyclic compounds, such as metyrapone, by arylating the alpha carbon atom of a ketone, to form a quaternary center thereat, would be an advance in the art.